Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years), and the incidence of childhood ALL has continuously increased in the United States since 1975. Genome-wide association studies (GWAS) have identified common variants in several genes that are significantly associated with the risk of developing ALL including ARID5B, IKZF1 and CEBPE. However, there are likely additional variants contributing to the heritability of ALL that current GWAS may not have been powered to detect. There is mounting evidence to suggest that stable and plastic epigenetic modification may also play an essential role in heritability of many cancers including leukemia. MicroRNA (miRNA), one epigenetic factor, post- transcriptionally regulates many biological mechanisms, such as apoptosis, adaptive and innate immunity. MicroRNA regulation has recently emerged as an important, yet under-explored, mechanism that can change the expression of multiple genes implicated in carcinogenesis. We hypothesize that miRNA modification is heritable and associated with ALL risk. Further, we postulate that variants within miRNAs and variants in corresponding miRNA binding sites contribute to the susceptibility of ALL and that interactions between variants in these two regions may contribute to ALL risk in a non-additive manner. To test these hypotheses, we will conduct extensive bioinformatics analyses of genotyping data from two large GWAS of childhood ALL completed in 2016, with more than 4500 cases and nearly 5000 controls across the Discovery and Replication datasets comprised primarily of Hispanics/Latinos and Whites, but also contain subjects of Asian and African- American ancestry. These subjects have been genotyped for more than 700,000 single-nucleotide polymorphisms across the genome. To increase the chance of observing polymorphisms within miRNAs, and to increase comparability between subjects genotyped on different genotyping platforms, we will conduct whole genome imputation prior to analysis. We will first identify variants within miRNA coding regions and miRNA binding sites that are associated with risk of ALL. We will then take a gene-based approach to identify rare variants (minor allele frequency less than 1%) in and around miRNA coding regions and miRNA binding sites that are associated with risk of ALL in aggregate. Finally, we will investigate if interactions between variants in miRNA coding regions and their specific miRNA biding sites and associated target gene contribute to ALL susceptibility. These aims investigating the role of inherited genetic variation in miRNA coding regions and miRNA binding sites done on a genome-wide scale will hopefully provide new insights into the role of miRNAs in the etiology of childhood ALL, a research area of public health significance given the continuously increasing incidence.